Trilineage Sequencing Reveals Complex TCRβ Transcriptomes in Neutrophils and Monocytes Alongside T Cells

Recent findings indicate the presence of T cell receptor (TCR)-based combinatorial immune receptors beyond T cells in neutrophils and monocytes/macrophages. In this study, using a semiquantitative trilineage immune repertoire sequencing approach as well as under rigorous bioinformatic conditions, we identify highly complex TCRβ transcriptomes in human circulating monocytes and neutrophils that separately encode repertoire diversities one and two orders of magnitude smaller than that of T cells. Intraindividual transcriptomic analyses reveal that neutrophils, monocytes, and T cells express distinct TCRβ repertoires with less than 0.1% overall trilineage repertoire sharing. Interindividual comparison shows that in all three leukocyte lineages, the vast majority of the expressed TCRβ variants are private. We also find that differentiation of monocytes into macrophages induces dramatic individual-specific repertoire shifts, revealing a surprising degree of immune repertoire plasticity in the monocyte lineage. These results uncover the remarkable complexity of the two phagocyte-based flexible immune systems which until now has been hidden in the shadow of T cells.